Dendrimers in anticancer targeted drug delivery: accomplishments, challenges and directions for future

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Abstract

Dendrimers are nanoparticles with unique features including globular 3D shape and nanometer size. The availability of numerous terminal functional groups and modifiable surface engineering permit modification of dendrimer surface with several therapeutic agents, diagnostic moieties and targeting substances.

The aim. To enlighten the readers regarding design, development, limitations, challenges and future directions regarding anticancer bio-dendrimers.

Materials and methods. The data base was represented by such systems as Medline, Cochrane Central Register of Controlled Trials, Scopus, Web of Science Core Collection, PubMed. gov, Google-Academy. A search was carried out for the following keywords and combinations: Polypropylene imine (PPI); Poly-L-lysine (PLL); Polyamidoamine (PAMAM); cancer; drug delivery; dendrimers.

Results. High encapsulation of drug and effective passive targeting are also among their therapeutic uses. Herein, we have described latest developments in chemotherapeutic delivery of drugs by dendrimers. For the most part, the potential and efficacy of dendrimers are anticipated to have considerable progressive effect on drug targeting and delivery.

Conclusion. The newest discoveries have shown that the dendritic nanocarriers have many unique features that endorse more research and development.

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Abbreviations: PPI – Polypropylene imine; PLL – Poly-L-lysine; PAMAM – Polyamidoamine; PDI – Polydispersity index; SiRNA – Small interfering ribonucleic acid; DOX – Doxorubicin; PTX – Paclitaxel; G4 – Generation 4; DTX – Docetaxel; TZ – Trastuzumab; HER2 – Human epidermal growth factor receptor type 2; FA – Folic acid; HABA – 4’-hydroxyazobenzene-2-carboxylic acid; DSC – Differential scanning calorimetry; rMETase – recombinant methioninase; DAB – 1,4-diaminobutane; scFvs – single chain fragment variables; Ara-C – Cytarabine; GL – Glycyrrhizin.

INTRODUCTION

Chemotherapeutic agents are administered to cancer patients with an intent to inhibit the growth of proliferating cells [1]. However, in many circumstances due to the lower extent of drug delivery, generalized delivery of drug to all parts of the body including areas which do not have tumors and various side effects, the expected aims and goals are not achieved. Nanomedicine is a field of science that deals with therapeutic agents/substances whose average particle size is in the range of nanometers [2]. In comparison to the traditional drug delivery agents including tablets, capsules etc, the design and development of targeted drug delivery systems has gained attention in the recent decades as they offer several advantages over their traditional counterparts [3, 4]. Although chemotherapeutic agents are available in the management and treatment of cancer however they possess numerous side effects and also exhibit weak anticancer activity. Moreover, these traditional systems cannot deliver the drug selectively to tumor interstitium. Novel drug delivery systems are designed keeping in mind the challenges faced by traditional chemotherapeutics and to address the issues related to them. The novel drug delivery systems include polymeric micelles, nanoparticles, liposomes and dendrimers, [5, 6] while some systems have found their way to the market such as Doxil© (liposomes loaded with doxorubicin) and Abraxane© (paclitaxel bound to albumin) [7].

Dendrimers are 3D globular molecules possessing a central core and from that core numerous arms originate with extensive branching [8, 9]. Compounds and conjugates to formulate dendrimers are synthesized sequentially step-by-step which provides uniform and even branching to molecules, specific groups on the surface, low polydispersity index (PDI) and unique molecular size. Hence dendrimers synthesized by stepwise process possess numerous advantages over polymers synthesized in single step. The first reporting of dendrimers was recorded almost 3 decades ago [10, 11], though early exploration only focused on their chemical and physical characteristics and the synthesis steps, and it was since the last decade when researchers started to discover their potential in the field of nanomedicine and other associated biomedical fields. Dendrimers have shown promise in many areas such as in chemotherapy, vaccine development, antivirals, antibacterials, siRNA/gene delivery and various diagnostic applications in medicine and health sector [12–15].

The structure of dendrimers is the key in offering benefits for biomedicine, drug delivery and diagnostic applications. Courtesy controlled multivalency of dendrimers, a plethora of drug molecules, targeting and solubilizing groups can be linked to their surface. Additionally, due to low dendritic PDI, they exhibit predictable/reproducible clinical pharmacokinetics in contrast to conventional linear polymers. Moreover, unlike dendrimers most traditional linear polymers exhibit uneven coiled structure, however the 3D globular dendritic structure influences biochemical properties, leading to positive outcomes related to their 3D macrostructure. Recently, synthetic or semisynthetic polymers have shown promise in drug delivery as polymeric micelles [16–18], this finding has motivated researchers working on dendrimers to synthesize new macromolecules in their design and development and possible exploration of novel chemotherapeutics.

THE AIM. This article is written aiming to enlighten the readers regarding design, development, limitations, challenges and future directions regarding anticancer bio-dendrimers.

MATERIALS AND METHODS

The data base was represented by such systems as Medline, Cochrane Central Register of Controlled Trials, Scopus, Web of Science Core Collection, PubMed, Google-Academy. A search was carried out for the following keywords and combinations: Polypropylene imine (PPI); Poly-L-lysine (PLL); Polyamidoamine (PAMAM); cancer; drug delivery; dendrimers.

RESULTS AND DISCUSSION

1. An overview of dendrimers as therapeutic, diagnostic, theranostic and targeted delivery agents

Targeting ligands, drugs and diagnostic agents are attached to dendrimers. Anticancer drug-loaded Drugs bound to dendrimers have been found at higher concentrations in the systemic circulation in addition to enhanced cellular transfection and circumvention of efflux transporter. For instance, At least 50 unbound cisplatin molecules need to be transfected into the cell to exhibit efficacy. Nevertheless, cisplatin-bound dendrimers were found to exhibit better efficacy at lower concentrations of the drug with decreased cytotoxicity.

1.1. Dendrimers in diagnosis of diseases

Apart from acting as potential drug delivery molecules dendrimers have also been explored in diagnostic and imaging applications in cancer treatment [19, 20]. Chemotherapy works either by one or a combination of these ways including angiogenesis inhibition, apoptosis induction, gene expression modulation, signal transduction inhibitor blockage and vaccines. Anticancer drugs can either be enclosed in the core (via hydrogen bonding, hydrophobic interaction or electrostatic attachment) or can be attached covalently to the surface/shell/branches to dendritic end groups [21]. The extent of drug loading depends on the generation of dendrimer being used: higher the generation better is the entrapment, moreover it also offers a plethora of functional groups for drug conjugation.

1.2. Drug release kinetics of dendrimers

The dendrimer-drug interaction governs the fate of drug release from the dendritic complex [22]. The rate of drug release from the core varies significantly from that of dendrimer end groups. Usually the drug bound to the surface releases first and at a faster pace while drug inside core is the last to be release and gives a sustained release effect. Furthermore, the pH and other environmental factors play a key role in drug release. Chemotherapeutic drugs act non selectively and cannot specifically target the tumor, a major challenge in the success of conventional chemotherapy. Henceforth, researchers have devised an approach to selectively target tumor, a strategy similar to antibody-toxin, immunoconjugate concept where potential units/molecules are first identified and then attached to the nanoparticulate/drug delivery system surface which propels the carrier towards the tumor directly without being distributed to all parts of body [23]. An important feature of this approach is to take DNA zipper which allows the targeting agent, e.g. folate targeted PAMAM [24], to be attached to dendritic complex by cDNA. Latest dendritic complexes which possess the capacity to attach carbohydrates are currently using these agents. A good example is the application of dendrimer in vaccine development where oligosaccharides (which are exclusive to cancer cells) are attached onto the dendrimer surface [25–28]. Recently, it has been found that dendrimers direct the carbohydrates’ multimeric presentation vital to enhancing the cluster glycoside effect (responsible for enhanced dendrimer targeting) [29–31]. An additional approach to apply glycosylation in cancer treatment involves sialic acid expression on cellular surface by the use of N-acetyl-mannosamine analogs [26, 32]. Dendrimers can load and attach a range of targeting agents which can direct them towards the cancer cells [33, 34]. Biocompatibility and safety of drug delivery systems has always been of concern, however dendrimers have been found to be safe and biocompatible and are easily eliminated out of body. The complexes of drug-PAMAM remain in systemic circulation for long in comparison to unbound free drug. The elimination pathway of dendrimers is renal and they are also used up by growth factors, folic acid, peptides and antibodies [35–39]. In some positively charged dendrimers, peripheral end groups have been found to cause toxicity against normal cells [40–42].

2. Dendrimer types

2.1 Poly(amidoamine) PAMAM dendrimers

Poly(amidoamine) PAMAM are the most commonly used dendrimers in drug deliver due to their hydrophilic, biocompatible and non-immunogenic nature. The cores of PAMAM dendrimers are usually made up of diaminododecane, ethylenediamine, diaminohexane and diaminobutane [43, 44]. The moieties which are used to fabricate branches comprise methyl acrylate and ethylenediamine, possess amine and carboxyl end groups [45].

2.1.1. Anticancer drug loaded PAMAM dendrimers: Doxorubicin (DOX)

One of the most frequently used drug in chemotherapy is doxorubicin. In spite of its numerous efficacious effects it exerts major adverse effects, the most dangerous of which is cardiotoxicity [46]. Many researchers around the globe have recently developed dendrimers for drug delivery and they have successfully loaded DOX onto them to reduce its adverse effects thereby increasing its efficacy [47–49]. Zhong et al. [50] while working on pulmonary drug delivery formulated DOX-loaded dendrimers and investigated their activity in decreasing the extent of metastasis when administered locally into lungs. Acid-sensitive hydrazone bonding was used to conjugate DOX to the surface of G4 PAMAM dendrimers. Mice were xenografted with melanoma B16-F10 cells to study the metastasis reducing effect of local pulmonary administration of DOX-loaded dendrimers, the size of tumor was found to be reduced with reduction in cardiac circulation of cancer cells, moreover, the pulmonary accumulation of DOX conjugated dendrimers was also found to be enhanced. The acid-responsive hydrazone bond between the dendrimers and drug helps in stimulus-sensitive release of drug release in tumor or endosomal vesicles [51] on low pH exposure thus enhancing tumor targeting and release.

2.1.2. Anticancer drug loaded PAMAM dendrimers: Paclitaxel (PTX)

In past two decades, researchers have thoroughly studied stimuli responsive drug release and a lot of progress has been made in this area [52, 53]. Working on this strategy [54] G4 PAMAM dendrimers were attached to PTX using a peptide linker (which can be cleaved by an enzyme cathepsin B in vivo), the PTX-loaded dendritic complex was found to be more cytotoxic to cancer cells (possessing high cathepsin B activity in comparison to normal cells) in contrast to unbound PTX. PTX-loaded dendrimers were found to exhibit better tumor inhibition efficacy than free drug in vivo in mice with actively expressing cathepsin B MDA-MB-231 xenograft.

2.1.3. Anticancer drug loaded PAMAM dendrimers: Docetaxel (DTX)

To improve the targeting ability of dendrimers such as PAMAM, their surface can be modified and attached with numerous ligands, this attachment results in offering better tumor targeting with reduced adverse effects [55]. One of the commonly used ligands in active targeting are the antibodies. Kulhari research group [56] used an antibody trastuzumab (TZ) as a ligand and conjugated it to surface of DTX-loaded G4 dendrimers using PEG as linking agent. Human epidermal growth factor receptor type 2 (HER2) are reported to be over expressed in numerous types of cancers, TZ being present on dendrimers surface gets attached to them and stop downstream signaling [57]. Two types of cells such as MDA-MB-453 (HER2 positive) and MDA-MB-231 (HER2 negative) were used to investigate the efficacy and targeting potential of TZ-bearing dendrimers. After a 4 h incubation period, in contrast to DTX-loaded dendrimer (without TZ), 70% higher cellular uptake of TZ-DTX dendrimers was seen in MDA-MB-453 (HER2 positive) cells, whereas no significant difference in cellular uptake was observed in MDA-MB-231 (HER2 negative) cells. Furthermore, in contrast to DTX-loaded dendrimer (without TZ), TZ-DTX dendrimers showed higher cytotoxicity against MDA-MB-453 cancer cells. Additionally, the IC50 exhibited by TZ-DTX dendrimers was found to be 3.6-fold greater than the DTX-loaded dendrimer (without TZ), though no considerable difference was observed in the efficacy of any of the formulations or the free drug in MDA-MB-123 cells.

2.1.4. Anticancer drug and siRNA co-loaded PAMAM dendrimers: DOX and siRNA

To address the issue of multidrug resistance (caused by protein P-gp) Pan research group [58] used P-gp analog siMDR-1 in co-delivery of anticancer drug DOX and siRNA and the initial results were promising. PEG-complexed G4 PAMAM dendrimers were co-loaded with siMDR-1 and DOX. PEG helps homogenizing the structure of dendrimers in addition to shielding the cationic charge. PAMAM assists in the complexation of siRNA, enhancing interaction with the cells and aiding in endosomal escape. To enhance the therapeutic potential, maintaining an equilibrium between interaction with cells and cytotoxicity is important. To co-deliver siRNA and DOX, the optimum ratio of MDM was discovered to be 1:10. MDM dendrimers (1:10) complexed with siMDR-1 were found to decrease the function and levels of membrane attached P-gp, hence resulting in decreased multidrug resistance. Together with effectively delivering siRNA to cancer cells and reducing multidrug resistance, the dendrimers also exhibited better cytotoxicity against cancer cells in comparison to free DOX.

2.1.5. PAMAM dendrimers in combination chemotherapy: DOX and Cisplatin

PAMAM dendrimers have been extensively explored in various aspects of drug delivery, an important area is the combination drug delivery. Guo and coworkers [59] studied the effect of loading a combination of chemotherapeutics onto dendrimers. To realize their idea, first they fabricated amine terminated G4 PAMAM dendrimers modified with hyaluronic acid (HA@PAMAM) followed by co-loading (covalent conjugation) of cisplatin and DOX (HA@PAMAM-Pt-Dox). By performing various studies and tests it was found that HA@PAMAM-Pt-Dox dendrimers enhanced the efficacy of cisplatin and DOX against breast cancer, the efficacy of HA@PAMAM-Pt-Dox was found to be better than free/unbound cisplatin and DOX combination. Notwithstanding numerous achievements and gains, some challenges were also encountered in this strategy including lack of targeted delivery to cancer cells, drug solubility issues and occasionally issues faced due to drugs’ antagonistic nature. The researchers thoroughly studied the physicochemical characteristics of HA@PAMAM-Pt-Dox dendrimers both in vitro and in vivo and the results positively indicated their synergistic potential in breast cancer therapy.

2.1.6. PH-responsive PAMAM dendrimers surface-decorated with FA in DOX delivery

Working on stimuli-responsive drug release Zhang and coworkers [60] selected partially acetylated G5 PAMAM dendrimers, conjugated folic acid onto the surface followed by DOX conjugation by a pH-sensitive cis-aconityl linkage yielding G5.NHAc-FA-DOX conjugate. FA receptors are known to be overexpressed in a variety of cancers and this is the rationale behind attaching FA onto the surface of drug delivery agents so that they could offer cancer targeting. The fabricated dendrimers co-loaded with DOX and folic acid showed promise in reducing the severity and growth of tumor.

2.1.7. Biotinylated PAMAM dendrimers for Paclitaxel (PTX) delivery

Alongside DOX, researchers have worked on other chemotherapeutics as well to enhance their efficacy and reduce their side effects, Yao and Ma [61] strived to improve cell uptake and reduce unwanted adverse effects of Paclitaxel. In doing so, they performed biotinylation of PAMAM dendrimers and conjugated paclitaxel (PTX) onto them. To assess the level of dendritic biotinylation, 4’-hydroxyazobenzene-2-carboxylic acid (HABA) assay was performed. HABA assay results confirmed a comprehensive dendritic biotinylation. To confirm the retention of the complex’s basic integrity, differential scanning calorimetry (DSC) was performed which confirmed the integrity of complex. Following their development, various physicochemical tests including determination of drug loading (%) and in vitro drug release were performed to investigate characteristics of the PTX-biotinylated dendrimers complex. To investigate the cell transfection potential of PTX-biotinylated dendrimers in HEK293T and OVCAR-3, a study involving fluorescence was performed. The dendrimer complex exhibited high drug loading 12.09% and a sustained drug release 70% for 72 h in comparison to free drug and other formulations. OVCAR-3 (cancer) cells, in comparison to HEK293T (normal) cells up took more biotinylated dendrimers. Through a set of statistical and experimental studies and experiments it was found that the biotinylated dendrimers release the drug in a sustained manner for up to 72 hours, augmented the cellular uptake with lesser toxicity and adverse effects.

2.1.8. PAMAM dendrimers surface-decorated with Hyaluronic acid (HA) for recombinant methioninase (rMETase) delivery

Li and coworkers [49] strived to deliver chemotherapeutics to gastric cancer (GC), one of the most common causes of cancer-associated deaths. Against GC, recombinant methioninase (rMETase) is commonly used anticancer drug in polymer based nanoparticulate delivery. The researchers developed a novel dendritic drug delivery system comprising G5 PAMAM-Au-METase and surface modified it with Hyaluronic acid (HA), the system exhibited promising biocompatibility, solubility and other characteristics. In an in vivo study carried out in Nu/Nu nude mice xenografted with CD44(+) GC cells, HA decorated G5 PAMAM-Au-METase dendrimers were seen to decrease the size of tumor and inhibiting its growth.

2.1.9. PAMAM dendrimers modified with Alkyl PEG and Cholesteryl formate

Pishavar research group [62] modified G5 PAMAM dendrimers into two different ways such as alkyl-PEG and cholesteryl formate modification, additionally they also surface-modified G4 PAMAM with tumor necrosis factor receptor-associated apoptosis-inducing ligand for targeted colon cancer delivery. The resultant modified dendrimers showed better transfection efficiency by overcoming numerous barriers (both extracellular and intracellular) in addition to reducing the toxicity of PAMAM. Furthermore, an in vivo study performed in mice bearing C26 tumor xenografts showed the tumor inhibitory potential of the dendritic drug delivery system. An important aspect related to different generations of PAMAM dendrimers is maintaining an equilibrium between the efficacy and toxicity, usually the higher the generation so is the efficacy and toxicity. Considering this factor, many researchers are using G4 PAMAM dendrimers as drug and siRNA/ gene delivery agents owing to their better efficacy and moderate toxicity.

2.2. Poly (propylene imine) PPI dendrimers

After PAMAM, PPI dendrimers are commonly used and they contain a core which is usually made up of 1,4-diaminobutane (DAB), however it can also be synthesized using ethylenediamine or other agents and by double Michael addition. Propylene imine monomers are frequently used as branching units in these dendrimers. Thus, their core is composed of tertiary tris propylene amine monomers, and the surface ends are usually made up of primary amines [64]. In contrast to PAMAM, their core is more hydrophobic due to the presence of alkyl chains and amide groups [65].

2.2.1. PPI dendrimers encapsulated with anticancer drug: Melphalan

Kesherwani research group worked on different generations of PPI dendrimers and also modified them [66, 67]. G3, G4 and G5 PPI dendrimers were encapsulated with melphalan and G4 and G5 complexes exhibited better inhibition of tumor and prolonged survival in BALB/c mice bearing MCF-7 cell xenografts. As the generation number goes up, so does the hemolytic toxicity of the dendrimers [68]. The targeting ability of these PPI dendrimers was found to be enhanced on FA surface modification, moreover their efficacy was also augmented and toxicity reduced possibly due to cationic group concealment by FA. However, the biocompatibility of G5 was found to be compromised in contrast to lower generations such as G3 and G4. Furthermore, dendrimers surface modified with FA showed better tumor inhibition in BALB/c mice bearing MCF-7 xenografts.

2.2.2. PPI dendrimers encapsulated with PTX and surface decorated with monoclonal antibody

To enhance the targeting efficiency of PPI dendrimers, Jain and coworkers [69] fabricated carboxylic acid-terminated G4.5 PPI dendrimers, surface-decorated them with monoclonal antibody mAbK1 for better targeting and loaded them with chemotherapeutic drug PTX (mAbK1-PPI-PTX). Mesothelin is a protein which has been found to be overexpressed in certain cancers and mAbK1 specifically binds to it. mAbK1-PPI-PTX dendrimers showed better cytotoxicity in vitro in OVCAR-3 (mesothelin overexpressed ovarian cancer) cells in comparison to free PTX or PPI-PTX dendrimers. It can be concluded from the findings of numerous physicochemical and in vitro experiments that the PTX-loaded G4.5 PPI immune-dendrimers possess potential to efficiently target ovarian cancer cells due to the overexpression of mesothelin receptors on them.

2.2.3. Maltose-modified PPI dendrimers (mal-PPI) surface complexed with siRNA

Tietz research group [70] while working on short interfering RNAs (siRNAs) found their application in cancer treatment. They worked on the development of new polymer nanocarrier built up of transfection disabled maltose-modified PPI dendrimers (mal-PPI) attached to single chain fragment variables (scFvs) for the targeted siRNA delivery. The results showed mal-PPI dendrimers to be efficient carriers of siRNA in cancer therapy, moreover this study also highlighted a novel strategy for bio-conjugation of nano-biomaterials to protein ligands.

2.2.4. PPI dendrimers loaded with anticancer drug: Cytarabine (Ara-C)

Szulc lab [71] worked to improve the already present strategies in leukemia treatment. Cytarabine, abbreviated as Ara-C is a chemotherapeutic drug, notwithstanding its efficacy it faces numerous challenges such as insufficient cellular uptake, buildup in tumor cells rather it should be converted to active triphosphate analogue, and the development of resistance. PPI dendrimers were complexed with nucleotide Ara-C triphosphate (Ara-CTP). PPI glycol-dendrimers efficiently loaded, carried and delivered cytarabine to cancer (1301 and HL-60 leukemia) cells in vitro. The results showed potential of the drug-PPI dendritic complex in targeted chemotherapy.

2.2.5. PPI dendrimers surface-decorated with Glycyrrhizin (GL) (GL-PPI) for DOX delivery

et al. [69] developed two different nanocarriers for the delivery of DOX i.e. GL-conjugated PPI dendrimer complex (GL-PPI-DOX) and GL decorated multi-walled carbon nanotubes (GL-MWCNT-DOX) in hepatic cancer. GL-PPI-DOX dendrimers showed better drug loading and entrapment efficiency (87.26±0.57%) in contrast to GL-MWCNT-DOX nanotubes (43.02±0.64%). Moreover, the hemolytic toxicity of DOX was also found to be decreased by 12.38±1.05% in case of GL-PPI-DOX and 7.30±0.63% while loaded onto GL-MWCNT-DOX, and the possible explanation of this phenomenon is the presence of GL in nanocarriers. An in vitro (MTT) assay carried out on HepG2 cells exhibited a decrease in the IC50 of DOX from 4.19±0.05 μM (of free dox) to 2.7±0.03 in case of GL-MWCNT-DOX and 2.0±0.01 μM for DOX loaded onto GL-PPI-DOX.

 

Table 1 – Dendrimers in targeted chemotherapy

Dendrimer complex

Cancer type

Payload (Drug/siRNA/gene)

Significant outcomes and findings

Type of Study

Reference

Dendrimers coated with gold nanoparticles

Breast

Curcumin

Reduction in growth and tumor size

In vitro

[70]

PAMAM-phosphorous dendrimers

Polo-like kinase 1 siRNA-607

Effective siRNA delivery to tumor interstitium

In vitro

[71]

Biotinylated PAMAM-PEG dendrimers

Lung

Paclitaxel

Successful targeted delivery of PTX to biotin receptors

In vitro

[72]

Peptide labeled dendrimers

A complex of DNA-Plasmid

Effective gene therapy in vivo in RAG1KO mice bearing lung cancer xenografts

In vitro & In vivo

[73]

PEG-immobilized, or

PEGylated, surfaces and PAMAM dendrimer-immobilized

Glycoprotein-enzyme

Cancer cell detection using enzymes

In vitro

[74]

FA-decorated PAMAM dendrimers

cis-diamine platinum and siRNA

Effective receptor-mediated targeted co-delivery of cis-diamine platinum and siRNA

In vitro

[75]

Alkyl-modified dendrimers

siRNA

Successful siRNA delivery and gene silencing

In vitro

[76]

PAMAM dendrimers

Skin

antisense oligonucleotide

Effective apoptosis in skin cancer

In vitro & in vivo

[77]

Phosphorous dendrimer

Methylene blue and rose Bengal

Successful skin cancer therapy

In vitro

[78]

Biotinylated-PAMAM dendrimers

cRGD peptide

Successful development of dendrimers for Integrin αVβ3 targeting

In vitro

[38]

Akali blue-PAMAM dendrimers

Lymphoma

Paclitaxel

Successful diagnosis and targeted lymphoma therapy

In vitro

[39]

PAMAM dendrimers grafted with fatty acid

5-FU

Efficient Lymph absorption and enhanced 5-FU bioavailability

In vitro & In vivo

[79]

Lipids-based dendrimers

Ovarian

Lipids-based dendrimers

Successful theranostic applications

In vitro & In vivo

[80]

Herceptin- and Diglycolamic acid-functionalized PAMAM dendrimers

Cisplatin

Enhanced ovarian cancer targeting tumor inhibition

In vitro & In vivo

[69, 81]

PPI immuno-dendrimers

Paclitaxel

Antibody-mediated ovarian cancer targeting and tumor inhibition

In vitro & In vivo

[69, 82]

PAMAM-peptide dendrimers

Follicle-stimulating hormone receptor (FSHR)

FSH33-mediated ovarian cancer targeted delivery

In vitro & In vivo

[69, 83]

PAMAM-chitosan dendrimers

Brain

Temozolomide

Successful brain glioblastoma treatment

In vitro & In vivo

[84]

Concanavalin-, Sialic acid-, glucosamine-anchored PPI dendrimers

Paclitaxel

Augmented targeted delivery of paclitaxel to brain

In vitro & In vivo

[85]

PAMAM dendrimer modified with borneol (Bo) and FA

Doxorubicin

Successful brain glioma delivery

In vitro & In vivo

[20, 86]

Anti-EGFR dendrimers

siRNA

Enhanced in vivo siRNA brain delivery and gene silencing

In vitro & In vivo

[87]

Boronated-PAMAM dendrimer

Cetuximab

Effective neutron capture therapy of glioma

In vitro & In vivo

[88]

 

2.3. Poly-l-lysine PLL dendrimers

Because of their promising oligonucleotide condensation potential, poly-L-lysine (PLL) dendrimers are frequently employed in siRNA and gene delivery applications [89]. Like other polymers (PAMAM and PPI) used to fabricate dendrimers, PLL also exhibits promising hydrophilic characteristic, elasticity, biocompatibility and biodegradability. The core and the branching monomers are both made up of amino acid lysine, and structural peptide bonds are also prevalent [90]. PLL dendrimers differ from PAMAM and PPI in their asymmetrical nature. However, they still possess specificity with the presence of terminal amine groups and arranged/sequenced number of lysine groups emanating from core. Lysine present in terminal PLL contains two modifiable primary amines that can be functionalized for improved biomedical applications [91, 92].

2.3.1. PLL dendrimers loaded with anticancer drug: DOX

DOX can be successfully loaded onto PLL dendrimers and its targeted delivery can also be realized resulting in better chemotherapeutic activity and less adverse effects [66, 92]. G6 PLL dendrimers (without carrying any drug) with strong cationic charge showed efficient in vivo anticancer activity in mice bearing B16F10 xenografts [93]. Another study found these dendrimers to exhibit deep in vivo penetration in mice bearing B16F10 melanoma xenografts and in vitro 3D DU145 prostate cancer tumor model, accrediting to their small average diameter and strong cationic charge [94, 95]. Li research group [96] also strived to improve DOX targeted delivery by using G6 PLL dendrimers. Niidome et al. [97] found higher PLL dendrimers tumor accumulation and reduction in tumor size in vivo in BALB/cN mice bearing Colon-26 mouse rectum carcinoma xenografts, with apparently no adverse effects. The attachment of PEG to PLL dendrimers resulted in improved accumulation in tumor by enhanced permeation and retention (EPR) effect, while the presence of oligopeptide bond created a hydrophobic cavity leading to enhanced DOX encapsulation. Some PLL dendrimers are in Phase I clinical trials such as a PEGylated-PLL dendritic delivery system surface-modified with docetaxel DEP® (Starpharma, Australia) exhibited improved targeted delivery and tumor (breast, ovarian, lung and prostate) inhibition efficiency than that by Taxotere® (docetaxel), an established anticancer drug [88]. Jain lab also studied the chemotherapeutic potential of PLL dendrimers in the treatment of cancer. The researchers developed PLL dendritic system surface decorated with FA (FPLL) as a DOX nanocarrier to enhance antiangiogenesis, tumor cell cytotoxity, targeted DOX delivery and a pH-responsive release. Ryan et al. [98] developed and compared the in vivo anti-lymphoma activities of three different drug delivery systems including PEGylated-PLL dendrimers loaded with DOX, DOX-loaded PEGylated liposomes and DOX-encapsulated pluronic micelles by studying their plasma and lymph pharmacokinetics. The results revealed that on subcutaneous and intravenous dosing the PEGylated-PLL dendrimers substantially augmented the recovery of DOX in thoracic lymph better than the DOX-encapsulated pluronic micelles.

2.3.2. PLL dendrimers surface-complexed with siRNA

PLL possesses potential to efficiently attach and condense siRNA/gene on to its surface, a characteristic courtesy which it has gained a lot of attention by researchers. Patil and coworkers developed a triblock PAMAM-PEG-PLL dendritic system for targeted siRNA delivery and gene silencing. Each monomer of the triblock was carefully selected and had certain roles to play for instance PAMAM acted as a proton sponge and aided in endosomal escape and the cytoplasmic delivery of siRNA; likewise PEG linked PLL to PAMAM, provided stability against nucleases and also helped retain siRNA integrity in plasma; moreover, PLL provided enhanced transfection and penetration, and strong siRNA binding onto the surface by the presence of primary amines. Apparently no toxicity related to the triblock polymer was reported, moreover the toxicity of PLL was also found to be significantly reduced, and the possible explanation to this observation is PEG-PAMAM conjugation. The findings revealed promising transfection efficiency of the triblock PAMAM-PEG-PLL dendritic system into cancer cells and also exhibited significant stability in plasma.

CONCLUSION

Dendrimers have seen considerable growth and progress in their design and development for biomedical applications during last two decades. Dendrimers, due to their globular structure and polyvalent character possess potential to address the challenges and problems faced by conventional drug delivery such as poor solubility, non-selective delivery and poor bioavailability and distribution. Moreover, dendrimers have also recently shown promise in the areas of imaging; diagnostics, theranostics, targeting drug delivery and others.

An area that still needs an in depth analysis and attention of researchers is acquiring more information regarding the bioavailability and distribution of dendrimers so that these characteristics could be optimized for best effect. Dendrimers when administered in vivo should be able to stay in plasma long enough to gather at the target sites, nonetheless their timely elimination out of the body is also equally important to avoid causing toxicity or other adverse effects, these areas need further attention and research. Another major challenge is to predict the fate of dendrimers (tissue localization) in vivo in advance; additionally, the effect of peripheral groups on the physicochemical properties of dendrimers also needs to be studied in depth. Drug release and kinetics is another field which needs more attention of researchers and can be significantly improved in getting more predictable and reproducible. The alteration/modification of enzymatically cleavable links in dendrimers is challenging due to compressed 3D globular dendrimer structure; nonetheless, dendrimers are useful platforms for using alternate release pathways such as cascade release. Few researchers have reported their findings lately in this area; however, more studies are needed to draw a conclusion.

The unique characteristics, qualities and advantages of large dendrimers over other linear polymers lie behind their stepwise synthesis; newest discoveries have shown that the dendritic nanocarriers have many unique features that endorse more research and development.

FUNDING

This review did not have external funding.

CONFLICT OF INTERESTS

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTION

M.W. Amjad – planning, collection of review materials, writing and editing the review.

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About the authors

Muhammad W. Amjad

Northern Border University

Author for correspondence.
Email: mwbamjad@yahoo.com
ORCID iD: 0000-0002-5832-8602

Assistant Professor, Department of Pharmaceutics, Faculty of Pharmacy

Saudi Arabia, Rafha, 76322

References

  1. Jabir NR, Tabrez S, Ashraf GM, Shakil S, Damanhouri GA, Kamal MA. Nanotechnology-based approaches in anticancer research. Int J Nanomedicine. 2012;7:4391–408. doi: 10.2147/IJN.S33838.
  2. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology. 2007; 2(12), 751–760. doi: 10.1038/nnano.2007.387.
  3. Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009;30(11):592–599. doi: 10.1016/j.tips.2009.08.004.
  4. Sutradhar KB, Amin ML. Nanoemulsions: increasing possibilities in drug delivery. Eur J Nanomedicine. 2013;5(2):97–110. doi: 10.1515/ejnm-2013-0001.
  5. Liu Z, Sun X, Nakayama-Ratchford N, Dai H. Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery. ACS Nano. 2007;1(1):50–56. doi: 10.1021/nn700040t.
  6. Popov AM, Lozovik YE, Fiorito S, Yahia L. Biocompatibility and applications of carbon nanotubes in medical nanorobots. Int J Nanomedicine 2007;2(3):361–372.
  7. Nagahara LA, Lee JS, Molnar LK, Panaro NJ, Farrell D, Ptak K, Alper J, Grodzinski P. Strategic workshops on cancer nanotechnology. Cancer Res. 2010 Jun 1;70(11):4265–8. doi: 10.1158/0008-5472.CAN-09-3716.
  8. Choudhary S, Gupta L, Rani S, Dave K, Gupta U. Impact of Dendrimers on Solubility of Hydrophobic Drug Molecules. Front. Pharmacol. 2017;8:261. doi: 10.3389/fphar.2017.00261.
  9. Kaga S, Arslan M, Sanyal R, Sanyal A. Dendrimers and Dendrons as Versatile Building Blocks for the Fabrication of Functional Hydrogels. Molecules. 2016 Apr 15;21(4):497. doi: 10.3390/molecules21040497.
  10. Tomalia, DA, Baker H, Dewald J, Hall M, Kallos G, Martin S, Roeck J, Ryder J, Smith P. A new class of polymers: starburst-dendritic macromolecules. Polym J. 1985;17:117–132.
  11. Newkome GR, Yao Z, Baker GR, Gupta VK. Cascade molecules: a new approach to micelles. A [27]-Arborol. J Org Chem. 1985;50:2003–2004. doi: 10.1021/jo00211a052
  12. Aulenta F, Hayes W, Rannard S. Dendrimers: a new class of nanoscopic containers and delivery devices. Eur Polym J. 2003;39:1741–1771.
  13. Stiriba S, Frey H, Haag R. Dendritic polymers in biomedical applications: from potential to clinical use in diagnostics and therapy. Angew Chem Int Ed Engl. 2002;41:1329–1334. doi: 10.1002/1521-3773(20020415)41:8<1329::aid-anie1329>3.0.co;2-p.
  14. Patri AK, Majoros IJ, Baker JR. Dendritic polymer macromolecular carriers for drug delivery. Curr Opin Chem Biol. 2002 Aug;6(4):466-71. doi: 10.1016/s1367-5931(02)00347-2.
  15. Boas U, Heegaard PM. Dendrimers in drug research. Chem Soc Rev. 2004 Jan 10;33(1):43-63. doi: 10.1039/b309043b.
  16. Wang YS, Youngster S, Grace M, Bausch J, Bordens R, Wyss DF. Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Adv Drug Deliv Rev. 2002 Jun 17;54(4):547-70. doi: 10.1016/s0169-409x(02)00027-3.
  17. Molineux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des. 2004;10(11):1235-44. doi: 10.2174/1381612043452613.
  18. Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov. 2003 May;2(5):347–60. doi: 10.1038/nrd1088.
  19. Jain K, Kesharwani P, Gupta U, Jain NK. A review of glycosylated carriers for drug delivery. Biomaterials. 2012 Jun;33(16):4166–86. doi: 10.1016/j.biomaterials.2012.02.033.
  20. Li T, Smet M, Dehaen W, Xu H. Selenium-Platinum Coordination Dendrimers with Controlled Anti-Cancer Activity. ACS Appl Mater Interfaces. 2016 Feb 17;8(6):3609–14. doi: 10.1021/acsami.5b07877.
  21. Cavell TA, Elledge LC, Malcolm KT, Faith MA, Hughes JN. Relationship quality and the mentoring of aggressive, high-risk children. J Clin Child Adolesc Psychol. 2009 Mar;38(2):185–98. doi: 10.1080/15374410802698420.
  22. Allen E, Howell MD. miRNAs in the biogenesis of trans-acting siRNAs in higher plants. Semin Cell Dev Biol. 2010 Oct;21(8):798–804. doi: 10.1016/j.semcdb.2010.03.008.
  23. Choi Y, Thomas T, Kotlyar A, Islam MT, Baker JR Jr. Synthesis and functional evaluation of DNA-assembled polyamidoamine dendrimer clusters for cancer cell-specific targeting. Chem Biol. 2005 Jan;12(1):35–43. doi: 10.1016/j.chembiol.2004.10.016.
  24. Quintana A, Raczka E, Piehler L, Lee I, Myc A, Majoros I, Patri AK, Thomas T, Mulé J, Baker JR Jr. Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm Res. 2002 Sep;19(9):1310–6. doi: 10.1023/a:1020398624602.
  25. Allen JR, Harris CR, Danishefsky SJ. Pursuit of optimal carbohydrate-based anticancer vaccines: preparation of a multiantigenic unimolecular glycopeptide containing the Tn, MBr1, and Lewis(y) antigens. J Am Chem Soc. 2001 Mar 7;123(9):1890–7. doi: 10.1021/ja002779i.
  26. Kudryashov V, Glunz PW, Williams LJ, Hintermann S, Danishefsky SJ, Lloyd KO. Toward optimized carbohydrate-based anticancer vaccines: epitope clustering, carrier structure, and adjuvant all influence antibody responses to Lewis(y) conjugates in mice. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3264–9. doi: 10.1073/pnas.051623598.
  27. Roy R, Baek MG. Glycodendrimers: novel glycotope isosteres unmasking sugar coding. case study with T-antigen markers from breast cancer MUC1 glycoprotein. J Biotechnol. 2002 May;90(3-4):291–309. doi: 10.1016/s1389-0352(01)00065-4.
  28. Toyokuni T, Hakomori S, Singhal AK. Synthetic carbohydrate vaccines: synthesis and immunogenicity of Tn antigen conjugates. Bioorg Med Chem. 1994 Nov;2(11):1119–32. doi: 10.1016/s0968-0896(00)82064-7.
  29. Kiessling LL, Pohl NL. Strength in numbers: non-natural polyvalent carbohydrate derivatives. Chem Biol. 1996 Feb;3(2):71-7. doi: 10.1016/s1074-5521(96)90280-x.
  30. Lundquist JJ, Toone EJ. The cluster glycoside effect. Chem Rev. 2002 Feb;102(2):555–78. doi: 10.1021/cr000418f.
  31. Yarema KJ, Bertozzi CR. Chemical approaches to glycobiology and emerging carbohydrate-based therapeutic agents. Curr Opin Chem Biol. 1998 Feb;2(1):49–61. doi: 10.1016/s1367-5931(98)80035-5.
  32. Keppler OT, Horstkorte R, Pawlita M, Schmidt C, Reutter W. Biochemical engineering of the N-acyl side chain of sialic acid: biological implications. Glycobiology. 2001 Feb;11(2):11R–18R. doi: 10.1093/glycob/11.2.11r.
  33. Mahal LK, Yarema KJ, Bertozzi CR. Engineering chemical reactivity on cell surfaces through oligosaccharide biosynthesis. Science. 1997 May 16;276(5315):1125–8. doi: 10.1126/science.276.5315.1125.
  34. Nauman DA, Bertozzi CR. Kinetic parameters for small-molecule drug delivery by covalent cell surface targeting. Biochim Biophys Acta. 2001 Dec 5;1568(2):147–54. doi: 10.1016/s0304-4165(01)00211-2.
  35. Thomas TP, Shukla R, Kotlyar A, Liang B, Ye JY, Norris TB, Baker JR Jr. Dendrimer-epidermal growth factor conjugate displays superagonist activity. Biomacromolecules. 2008 Feb;9(2):603–9. doi: 10.1021/bm701185p.
  36. Shi X, Wang SH, Van Antwerp ME, Chen X, Baker JR Jr. Targeting and detecting cancer cells using spontaneously formed multifunctional dendrimer-stabilized gold nanoparticles. Analyst. 2009 Jul;134(7):1373–9. doi: 10.1039/b902199j.
  37. Hill E, Shukla R, Park SS, Baker JR Jr. Synthetic PAMAM-RGD conjugates target and bind to odontoblast-like MDPC 23 cells and the predentin in tooth organ cultures. Bioconjug Chem. 2007 Nov-Dec;18(6):1756–62. doi: 10.1021/bc0700234.
  38. Lesniak WG, Kariapper MS, Nair BM, Tan W, Hutson A, Balogh LP, Khan MK. Synthesis and characterization of PAMAM dendrimer-based multifunctional nanodevices for targeting alphavbeta3 integrins. Bioconjug Chem. 2007 Jul-Aug;18(4):1148–54. doi: 10.1021/bc070008z.
  39. Thomas TP, Patri AK, Myc A, Myaing MT, Ye JY, Norris TB, Baker JR Jr. In vitro targeting of synthesized antibody-conjugated dendrimer nanoparticles. Biomacromolecules. 2004 Nov-Dec;5(6):2269-74. doi: 10.1021/bm049704h.
  40. Chen HT, Neerman MF, Parrish AR, Simanek EE. Cytotoxicity, hemolysis, and acute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drug delivery. J Am Chem Soc. 2004 Aug 18;126(32):10044–8. doi: 10.1021/ja048548j.
  41. Allen JR, Allen JG, Zhang XF, Williams LJ, Zatorski A, Ragupathi G, Livingston PO, Danishefsky SJ. A second generation synthesis of the MBr1 (globo-H) breast tumor antigen: new application of the n-pentenyl glycoside method for achieving complex carbohydrate protein linkages. Chemistry. 2000 Apr 14;6(8):1366–75. doi: 10.1002/(sici)1521-3765(20000417)6:8<1366::aid-chem1366>3.0.co;2-k.
  42. Young KA, Liu Y, Wang Z. The neurobiology of social attachment: A comparative approach to behavioral, neuroanatomical, and neurochemical studies. Comp Biochem Physiol C Toxicol Pharmacol. 2008 Nov;148(4):401–10. doi: 10.1016/j.cbpc.2008.02.004.
  43. Chang H, Wang H, Shao N, Wang M, Wang X, Cheng Y. Surface-engineered dendrimers with a diaminododecane core achieve efficient gene transfection and low cytotoxicity. Bioconjug Chem. 2014 Feb 19;25(2):342–50. doi: 10.1021/bc400496u.
  44. Esfand R, Tomalia DA. Poly(amidoamine) (PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications. Drug Discov Today. 2001 Apr 1;6(8):427–436. doi: 10.1016/s1359-6446(01)01757-3.
  45. Zhu S, Hong M, Zhang L, Tang G, Jiang Y, Pei Y. PEGylated PAMAM dendrimer-doxorubicin conjugates: in vitro evaluation and in vivo tumor accumulation. Pharm Res. 2010 Jan;27(1):161–74. doi: 10.1007/s11095-009-9992-1.
  46. Takemura SY, Nern A, Chklovskii DB, Scheffer LK, Rubin GM, Meinertzhagen IA. The comprehensive connectome of a neural substrate for ‘ON’ motion detection in Drosophila. Elife. 2017 Apr 22;6:e24394. doi: 10.7554/eLife.24394.
  47. Aher N, Banerjee S, Bhansali S, Yadav R, Shidore M, Mhaske S, Chaudhari R, Asai S, Jalota-Badhwar A, Khandare J. Poly(ethylene glycol) versus dendrimer prodrug conjugates: influence of prodrug architecture in cellular uptake and transferrin mediated targeting. J Biomed Nanotechnol. 2013 May;9(5):776–89. doi: 10.1166/jbn.2013.1582.
  48. Araújo RV, Santos SDS, Igne Ferreira E, Giarolla J. New Advances in General Biomedical Applications of PAMAM Dendrimers. Molecules. 2018 Nov 2;23(11):2849. doi: 10.3390/molecules23112849.
  49. Wang K, Zhang X, Liu Y, Liu C, Jiang B, Jiang Y. Tumor penetrability and anti-angiogenesis using iRGD-mediated delivery of doxorubicin-polymer conjugates. Biomaterials. 2014 Oct;35(30):8735–47. doi: 10.1016/j.biomaterials.2014.06.042.
  50. Zhong Q, Bielski ER, Rodrigues LS, Brown MR, Reineke JJ, da Rocha SR. Conjugation to Poly(amidoamine) Dendrimers and Pulmonary Delivery Reduce Cardiac Accumulation and Enhance Antitumor Activity of Doxorubicin in Lung Metastasis. Mol Pharm. 2016 Jul 5;13(7):2363–75. doi: 10.1021/acs.molpharmaceut.6b00126.
  51. Kale AA, Torchilin VP. Design, synthesis, and characterization of pH-sensitive PEG-PE conjugates for stimuli-sensitive pharmaceutical nanocarriers: the effect of substitutes at the hydrazone linkage on the ph stability of PEG-PE conjugates. Bioconjug Chem. 2007 Mar-Apr;18(2):363–70. doi: 10.1021/bc060228x.
  52. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013 Nov;12(11):991–1003. doi: 10.1038/nmat3776.
  53. Palmerston Mendes L, Pan J, Torchilin VP. Dendrimers as Nanocarriers for Nucleic Acid and Drug Delivery in Cancer Therapy. Molecules. 2017 Aug 23;22(9):1401. doi: 10.3390/molecules22091401.
  54. Satsangi G, Yadav S, Pipal AS, Kumbhar N. Characteristics of trace metals in fine (PM2.5) and inhalable (PM10) particles and its health risk assessment along with in-silico approach in indoor environment of India. Atmos Environ 2014;92:384–393. doi: 10.1016/j.atmosenv.2014.04.047
  55. Paz-Yaacov N, Bazak L, Buchumenski I, Porath HT, Danan-Gotthold M, Knisbacher BA, Eisenberg E, Levanon EY. Elevated RNA Editing Activity Is a Major Contributor to Transcriptomic Diversity in Tumors. Cell Rep. 2015 Oct 13;13(2):267–76. doi: 10.1016/j.celrep.2015.08.080.
  56. Kulhari H, Pooja D, Singh MK, Chauhan AS. Optimization of carboxylate-terminated poly(amidoamine) dendrimer-mediated cisplatin formulation. Drug Dev Ind Pharm. 2015 Feb;41(2):232–8. doi: 10.3109/03639045.2013.858735.
  57. Chung A, Cui X, Audeh W, Giuliano A. Current status of anti-human epidermal growth factor receptor 2 therapies: predicting and overcoming herceptin resistance. Clin Breast Cancer. 2013 Aug;13(4):223–32. doi: 10.1016/j.clbc.2013.04.001.
  58. Pan J, Mendes LP, Yao M, Filipczak N, Garai S, Thakur GA, Sarisozen C, Torchilin VP. Polyamidoamine dendrimers-based nanomedicine for combination therapy with siRNA and chemotherapeutics to overcome multidrug resistance. Eur J Pharm Biopharm. 2019 Mar;136:18–28. doi: 10.1016/j.ejpb.2019.01.006.
  59. Guo XL, Kang XX, Wang YQ, Zhang XJ, Li CJ, Liu Y, Du LB. Co-delivery of cisplatin and doxorubicin by covalently conjugating with polyamidoamine dendrimer for enhanced synergistic cancer therapy. Acta Biomater. 2019 Jan 15;84:367–377. doi: 10.1016/j.actbio.2018.12.007.
  60. Zhang M, Zhu J, Zheng Y, Guo R, Wang S, Mignani S, Caminade AM, Majoral JP, Shi X. Doxorubicin-Conjugated PAMAM Dendrimers for pH-Responsive Drug Release and Folic Acid-Targeted Cancer Therapy. Pharmaceutics. 2018 Sep 19;10(3):162. doi: 10.3390/pharmaceutics10030162.
  61. Yao H, Ma J. Dendrimer-paclitaxel complexes for efficient treatment in ovarian cancer: study on OVCAR-3 and HEK293T cells. Acta Biochim Pol. 2018;65(2):219–225. doi: 10.18388/abp.2017_2331.
  62. Pishavar E, Attaranzadeh A, Alibolandi M, Ramezani M, Hashemi M. Modified PAMAM vehicles for effective TRAIL gene delivery to colon adenocarcinoma: in vitro and in vivo evaluation. Artif Cells Nanomed Biotechnol. 2018;46(sup3):S503–S513. doi: 10.1080/21691401.2018.1500372.
  63. Tripathi PK, Tripathi S. Dendrimers for anticancer drug delivery. In Micro and Nano Technologies. 2020: 131–150. doi: 10.1016/B978-0-12-814527-2.00006-8.
  64. Bae S, Park J, Kim JS. Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases. Bioinformatics. 2014 May 15;30(10):1473–5. doi: 10.1093/bioinformatics/btu048.
  65. Shao N, Su Y, Hu J, Zhang J, Zhang H, Cheng Y. Comparison of generation 3 polyamidoamine dendrimer and generation 4 polypropylenimine dendrimer on drug loading, complex structure, release behavior, and cytotoxicity. Int J Nanomedicine. 2011;6:3361–72. doi: 10.2147/IJN.S27028.
  66. Al-Jamal KT, Al-Jamal WT, Wang JT, Rubio N, Buddle J, Gathercole D, Zloh M, Kostarelos K. Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo. ACS Nano. 2013 Mar 26;7(3):1905–17. doi: 10.1021/nn305860k.
  67. Kesharwani P, Tekade RK, Jain NK. Generation dependent safety and efficacy of folic acid conjugated dendrimer based anticancer drug formulations. Pharm Res. 2015 Apr;32(4):1438–50. doi: 10.1007/s11095-014-1549-2.
  68. Kesharwani P, Tekade RK, Jain NK. Generation dependent cancer targeting potential of poly(propyleneimine) dendrimer. Biomaterials. 2014 Jul;35(21):5539–48. doi: 10.1016/j.biomaterials.2014.03.064.
  69. Jain NK, Tare MS, Mishra V, Tripathi PK. The development, characterization and in vivo anti-ovarian cancer activity of poly(propylene imine) (PPI)-antibody conjugates containing encapsulated paclitaxel. Nanomedicine. 2015 Jan;11(1):207-18. doi: 10.1016/j.nano.2014.09.006.
  70. Malekmohammadi S, Hadadzadeh H. Immobilization of gold nanoparticles on folate-conjugated dendritic mesoporous silica-coated reduced graphene oxide nanosheets: a new nanoplatform for curcumin pH-controlled and targeted delivery. Soft Matter. 2018;14(12):2400–2410. doi: 10.1039/c7sm02248d.
  71. Jain A, Mahira S, Majoral JP, Bryszewska M, Khan W, Ionov M. Dendrimer mediated targeting of siRNA against polo-like kinase for the treatment of triple negative breast cancer. J Biomed Mater Res A. 2019 Sep;107(9):1933–1944. doi: 10.1002/jbm.a.36701.
  72. Rompicharla SVK, Kumari P, Bhatt H, Ghosh B, Biswas S. Biotin functionalized PEGylated poly(amidoamine) dendrimer conjugate for active targeting of paclitaxel in cancer. Int J Pharm. 2019 Feb 25;557:329–341. doi: 10.1016/j.ijpharm.2018.12.069.
  73. Holt GE, Daftarian P. Non-small-cell lung cancer homing peptide-labeled dendrimers selectively transfect lung cancer cells. Immunotherapy. 2018 Nov;10(16):1349–1360. doi: 10.2217/imt-2018-0078.
  74. Hsu HJ, Palka-Hamblin H, Bhide GP, Myung JH, Cheong M, Colley KJ, Hong S. Noncatalytic Endosialidase Enables Surface Capture of Small-Cell Lung Cancer Cells Utilizing Strong Dendrimer-Mediated Enzyme-Glycoprotein Interactions. Anal Chem. 2018 Mar 20;90(6):3670–3675. doi: 10.1021/acs.analchem.8b00427.
  75. Amreddy N, Babu A, Panneerselvam J, Srivastava A, Muralidharan R, Chen A, Zhao YD, Munshi A, Ramesh R. Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment. Nanomedicine. 2018 Feb;14(2):373–384. doi: 10.1016/j.nano.2017.11.010.
  76. Ayatollahi S, Salmasi Z, Hashemi M, Askarian S, Oskuee RK, Abnous K, Ramezani M. Aptamer-targeted delivery of Bcl-xL shRNA using alkyl modified PAMAM dendrimers into lung cancer cells. Int J Biochem Cell Biol. 2017 Nov;92:210–217. doi: 10.1016/j.biocel.2017.10.005.
  77. Venuganti VV, Saraswathy M, Dwivedi C, Kaushik RS, Perumal OP. Topical gene silencing by iontophoretic delivery of an antisense oligonucleotide-dendrimer nanocomplex: the proof of concept in a skin cancer mouse model. Nanoscale. 2015 Mar 7;7(9):3903–14. doi: 10.1039/c4nr05241b.
  78. Dabrzalska M, Benseny-Cases N, Barnadas-Rodríguez R, Mignani S, Zablocka M, Majoral JP, Bryszewska M, Klajnert-Maculewicz B, Cladera J. Fourier transform infrared spectroscopy (FTIR) characterization of the interaction of anti-cancer photosensitizers with dendrimers. Anal Bioanal Chem. 2016 Jan;408(2):535–44. doi: 10.1007/s00216-015-9125-0.
  79. Tripathi PK, Khopade AJ, Nagaich S, Shrivastava S, Jain S, Jain NK. Dendrimer grafts for delivery of 5-fluorouracil. Pharmazie. 2002 Apr;57(4):261-4.
  80. Liu Y, Ng Y, Toh MR, Chiu GNC. Lipid-dendrimer hybrid nanosystem as a novel delivery system for paclitaxel to treat ovarian cancer. J Control Release. 2015 Dec 28;220(Pt A):438–446. doi: 10.1016/j.jconrel.2015.11.004.
  81. Kesavan A, Ilaiyaraja P, Sofi Beaula W, Veena Kumari V, Sugin Lal J, Arunkumar C, Anjana G, Srinivas S, Ramesh A, Rayala SK, Ponraju D, Venkatraman G. Tumor targeting using polyamidoamine dendrimer-cisplatin nanoparticles functionalized with diglycolamic acid and herceptin. Eur J Pharm Biopharm. 2015 Oct;96:255–63. doi: 10.1016/j.ejpb.2015.08.001.
  82. Chopdey PK, Tekade RK, Mehra NK, Mody N, Jain NK. Glycyrrhizin Conjugated Dendrimer and Multi-Walled Carbon Nanotubes for Liver Specific Delivery of Doxorubicin. J Nanosci Nanotechnol. 2015 Feb;15(2):1088–100. doi: 10.1166/jnn.2015.9039.
  83. Modi DA, Sunoqrot S, Bugno J, Lantvit DD, Hong S, Burdette JE. Targeting of follicle stim ulating hormone peptide-conjugated dendrimers to ovarian cancer cells. Nanoscale. 2014;6(5):2812–2820.
  84. Sharma AK, Gupta L, Sahu H, Qayum A, Singh SK, Nakhate KT, Ajazuddin, Gupta U. Chitosan Engineered PAMAM Dendrimers as Nanoconstructs for the Enhanced Anti-Cancer Potential and Improved In vivo Brain Pharmacokinetics of Temozolomide. Pharm Res. 2018 Jan 2;35(1):9. doi: 10.1007/s11095-017-2324-y.
  85. Patel HK, Gajbhiye V, Kesharwani P, Jain NK. Ligand anchored poly(propyleneimine) dendrimers for brain targeting: Comparative in vitro and in vivo assessment. J Colloid Interface Sci. 2016 Nov 15;482:142–150. doi: 10.1016/j.jcis.2016.07.047.
  86. Xu X, Li J, Han S, Tao C, Fang L, Sun Y, Zhu J, Liang Z, Li F. A novel doxorubicin loaded folic acid conjugated PAMAM modified with borneol, a nature dual-functional product of reducing PAMAM toxicity and boosting BBB penetration. Eur J Pharm Sci. 2016 Jun 10;88:178–90. doi: 10.1016/j.ejps.2016.02.015.
  87. Agrawal A, Min DH, Singh N, Zhu H, Birjiniuk A, von Maltzahn G, Harris TJ, Xing D, Woolfenden SD, Sharp PA, Charest A, Bhatia S. Functional delivery of siRNA in mice using dendriworms. ACS Nano. 2009 Sep 22;3(9):2495–504. doi: 10.1021/nn900201e.
  88. Wu G, Yang W, Barth RF, Kawabata S, Swindall M, Bandyopadhyaya AK, Tjarks W, Khorsandi B, Blue TE, Ferketich AK, Yang M, Christoforidis GA, Sferra TJ, Binns PJ, Riley KJ, Ciesielski MJ, Fenstermaker RA. Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab. Clin Cancer Res. 2007 Feb 15;13(4):1260–8. doi: 10.1158/1078-0432.CCR-06-2399.
  89. Wu J, Huang W, He Z. Dendrimers as carriers for siRNA delivery and gene silencing: a review. ScientificWorldJournal. 2013 Oct 29;2013:630654. doi: 10.1155/2013/630654.
  90. Roberts BP, Scanlon MJ, Krippner GY, Chalmers DK. Molecular dynamics of poly(l-lysine) dendrimers with naphthalene disulfonate caps. Macromolecules. 2009;42(7):2775–2783. doi: 10.1021/ma802154e
  91. Choi JS, Nam K, Park JY, Kim JB, Lee JK, Park JS. Enhanced transfection efficiency of PAMAM dendrimer by surface modification with L-arginine. J Control Release. 2004 Oct 19;99(3):445–56. doi: 10.1016/j.jconrel.2004.07.027.
  92. Kaminskas LM, Kelly BD, McLeod VM, Sberna G, Owen DJ, Boyd BJ, Porter CJ. Characterisation and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker. J Control Release. 2011 Jun 10;152(2):241–8. doi: 10.1016/j.jconrel.2011.02.005.
  93. Al-Jamal KT, Al-Jamal WT, Akerman S, Podesta JE, Yilmazer A, Turton JA, Bianco A, Vargesson N, Kanthou C, Florence AT, Tozer GM, Kostarelos K. Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth. Proceedings of the National Academy of Sciences of the United States of America. 2010 Mar;107(9):3966–3971. doi: 10.1073/pnas.0908401107.
  94. Bugno J, Hsu HJ, Pearson RM, Noh H, Hong S. Size and Surface Charge of Engineered Poly(amidoamine) Dendrimers Modulate Tumor Accumulation and Penetration: A Model Study Using Multicellular Tumor Spheroids. Mol Pharm. 2016 Jul 5;13(7):2155–63. doi: 10.1021/acs.molpharmaceut.5b00946.
  95. Sunoqrot S, Liu Y, Kim DH, Hong S. In vitro evaluation of dendrimer-polymer hybrid nanoparticles on their controlled cellular targeting kinetics. Mol Pharm. 2013 Jun 3;10(6):2157–66. doi: 10.1021/mp300560n.
  96. Li J, Piehler LT, Qin D, Baker JR, Tomalia DA, Meier DJ. Visualization and characterization of poly(amidoamine) dendrimers by atomic force microscopy. Langmuir. 2000;16(13):5613–5616. doi: 10.1021/la000035c
  97. Niidome T, Yamauchi H, Takahashi K, Naoyama K, Watanabe K, Mori T, Katayama Y. Hydrophobic cavity formed by oligopeptide for doxorubicin delivery based on dendritic poly(L-lysine). J Biomater Sci Polym Ed. 2014;25(13):1362–73. doi: 10.1080/09205063.2014.938979.
  98. Ryan GM, Kaminskas LM, Bulitta JB, McIntosh MP, Owen DJ, Porter CJH. PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin. J Control Release. 2013 Nov 28;172(1):128–136. doi: 10.1016/j.jconrel.2013.08.004.

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СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 67428 от 13.10.2016. 

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